Calver, Andrew Robert; (1999) Oligodendrocyte population dynamics: Insights from transgenic mice. Doctoral thesis (Ph.D.), University College London.

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Abstract

The control of cell population size is a critical part of the development of any organism, and is a complex process involving cell division, migration and death. In addition to absolute cell numbers, the control of relative population sizes is of fundamental importance, as the different parts of an organism must develop in proportion to one another. I have attempted to address these questions using an in vivo model system; the oligodendrocyte lineage in the developing mouse spinal cord. Oligodendrocytes myelinate axons in the central nervous system (CNS). Their precursors originate in a restricted region in the ventral part of the developing spinal cord, and subsequently proliferate and migrate away from there to populate the entire spinal cord before differentiating into mature oligodendrocytes. It is not known what controls the number of proliferating progenitor cells, the timing and site of differentiation, or the number of their mature progeny. Platelet-derived growth factor-AA (PDGF-AA) is a potent mitogen for oligodendrocyte progenitor cells in vitro, but it was not known whether PDGF is important for oligodendrocyte development in vivo. I have shown by analysis of 'knockout' and transgenic mice that PDGF-AA is crucial for proliferation of oligodendrocyte progenitor cells in vivo, and that a decline in PDGF signalling is responsible for slowing of the cell cycle, withdrawal from the cycle and initiation of oligodendrocyte differentiation. I have also demonstrated that the number and location of mature spinal cord oligodendrocytes is controlled by selective cell survival, and is independent of progenitor cell proliferation. Excess and ectopic differentiating progenitors are cleared during normal development by programmed cell death, and as-yet-unidentified survival factors control the temporal and spatial appearance of mature oligodendrocytes. These data demonstrate the overriding importance of cell survival controls compared to cell proliferation controls for determining cell populations in the developing animal might be similarly regulated by selective cell survival and death.

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